Project Summary TB is the most common co-infection during HIV infection worldwide, and is associated with significant HIVrelated morbidity and mortality. Recent studies including those in HL-51636 have examined the basis of expansion of HIV during TB and at sites of dual HIV and M. tuberculosis (MTB) infection. Pleural TB in HIV/TB patients is an excellent disease model to study interactions of HIV with host mononuclear cells. Among pleural fluid mononuclear cells (PFMC), there is a massive expansion of effector and central memory T-cells which are particularly poised to HIV infection and viral expression. Mechanisms of HIV transcriptional activation of both CD4 T-cells and macrophages are supported in situ. Macrophages and dendritic cells (DC) contribute to increased HIV infection of MTB antigen specific CD4 T-cells, and increased regulatory T-cells (T-reg), suppress both MTB and HIV responses of effector T-cells in PFMC. Studies defining interactions of HIV proteins and host molecules in macrophages allow drug targeting for modulation of HIV/TB co-pathogenesis. HIV transcriptional activation in macrophages may be inhibited by a derivative of erythromycin, EM-703, by modulation of C/EBP&#946;&#61472;isoforms. Also, the CDK9 inhibitor Indirubicin Monoxime (IM), blocks transcriptional elongation of HIV by P-TEFb in both CD4 T-cells and macrophages. Further, the anti-neoplastic agent, Imatinib, improves apoptotic cell death of HIV-infected macrophages by counteraction to the pro-survival factor, M-CSF. Also, the role of regulatory T-cells (T-reg), recently established to be important in immunopathogenesis of HIV disease, and markedly expanded in situ in HIV/TB, in attenuation of immune circuits is now better understood. The Hypothesis of this proposal is that the milieu at sites of dual HIV/TB infection is conducive to increased HIV replication and spread by mononuclear phagocytes and DC, and the interface of HIV and host molecules is amenable to modulation through adjunctive anti-HIV therapies. Further, enrichment of T-reg in situ underlies suppression of protective responses and persistence of both pathogen. Specific Aims are: 1. To determine the mechanism(s) of enhanced HIV infection of MTB-specific CD4+ T cells by macrophages and DC in PFMC from HIV/TB dually infected patients. 2. To examine host factors and HIV molecules in promotion of HIV infection of mononuclear phagocytes in PFMC from dually infected HIV/TB subjects. To examine whether specific adjunctive therapies such as IM, or EM-703, or Imatinib that have been shown to have anti-HIV activity in macrophages are useful in control of HIV in PFMC from HIV/TB patients with pleural TB. 3. To examine the role of T-reg expanded at pleural sites of HIV/TB infection on immune responses to HIV infection, examine their contribution to viral persistence, and to the control of MTB growth at pleural sites of HIV/TB. Translational studies to assess the utility of anti-HIV adjunctive agents and to understand the role of T-reg may allow improved management of HIV/TB. Project